Solid dosage forms of palbociclib

ABSTRACT

The present invention relates to solid dosage forms of palbociclib comprising a water-soluble acid. The dosage forms described herein have desirable pharmacokinetic characteristics.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to solid dosage forms of6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one(hereinafter palbociclib), having desirable pharmacokineticcharacteristics which exhibit favorable storage stability anddissolution properties.

Description of Related Art

Palbociclib is a potent and selective inhibitor of CDK4 and CDK6, havingthe structure:

Palbociclib is described in WHO Drug Information, Vol. 27, No. 2, page172 (2013). Palbociclib and pharmaceutically acceptable salts thereofare disclosed in International Publication No. WO 2003/062236 and U.S.Pat. Nos. 6,936,612, 7,208,489 and 7,456,168; International PublicationNo. WO 2005/005426 and U.S. Pat. Nos. 7,345,171 and 7,863,278;International Publication No. WO 2008/032157 and U.S. Pat. No.7,781,583; and International Publication No. WO 2014/128588. Thecontents of each of the foregoing references are incorporated herein byreference in their entirety.

Palbociclib is approved in the United States for the treatment ofhormone receptor (HR)-positive, human epidermal growth factor 2(HER2)-negative advanced or metastatic breast cancer in combination withletrozole as initial endocrine therapy or in combination withfulvestrant following disease progression on endocrine therapy. The drugis sold by Pfizer under the trade name IBRANCE® in the form of animmediate release (IR) capsule dosage form comprising palbociclib as afree base for oral administration.

Palbociclib is a dibasic compound and has two basic groups with pKa's ofapproximately 7.3 (the secondary piperazine nitrogen) and 4.1 (thepyridine nitrogen). The solubility of palbociclib free base is pHdependent. Palbociclib is water soluble at low pH (2.1-4.5), while thesolubility dramatically decreases as pH rises above 4.5. Palbociclib haspoor water solubility (9 μg/mL) at pH 7.9. Concomitant administration ofagents which increase gastric pH can alter the solubility and absorptionof palbociclib free base formulations.

The absorption and bioavailability of a therapeutic agent can beaffected by numerous factors when dosed orally, including whether thesubject is in a fed or fasted state, and the use of certain medications,such as proton pump inhibitors (PPIs) or H2 receptor antagonists, aswell as certain medical conditions. Compounds having pH-dependentsolubility, particularly basic compounds, may exhibit undesirablepharmacokinetic properties, such as poor absorption and/or reducedbioavailability, which may result in significant inter-patient andintra-patient variability.

There remains a need to discover improved dosage forms of palbociclibhaving favorable dissolution and pharmacokinetic profiles, which alsodemonstrate good storage stability. We have surprisingly found that thesolid dosage forms according to the present invention demonstrateexcellent storage stability and provide substantially pH-independentdelivery of palbociclib with no significant food effects or adverseinteractions with PPIs.

BRIEF SUMMARY OF THE INVENTION

In a first aspect, the invention provides a solid dosage form comprisingpalbociclib, a water-soluble acid, and a pharmaceutically acceptablecarrier.

In a second aspect, the invention provides a solid dosage form of any ofthe embodiments described herein, wherein the dosage form when added toa test medium comprising 500 mL of 10 mM pH 5.5 acetate buffer at 37° C.in a standard USP 2 rotating paddle apparatus with the paddles spinningat 50 rpm dissolves: (a) not less than 35% of the palbociclib in 15minutes; (b) not less than 45% of the palbociclib in 30 minutes; (c) notless than 55% in 60 minutes; or (d) two or more of (a), (b) and (c).

In a third aspect, the invention provides a solid dosage form of any ofthe embodiments described herein, wherein the dosage form when added toa test medium comprising 500 mL of 50 mM pH 6.5 phosphate buffer and 0.1M NaCl at 37° C. in a standard USP 2 rotating paddle apparatus with thepaddles spinning at 50 rpm dissolves: (a) not less than 15% of thepalbociclib in 15 minutes; (b) not less than 20% of the palbociclib in30 minutes; (c) not less than 25% of the palbociclib in 60 minutes; or(d) two or more of (a), (b) and (c).

In some embodiments, the invention provides a solid dosage form of anyof the embodiments described herein, wherein the dosage form when addedto a test medium comprising 500 mL of 50 mM pH 6.5 phosphate buffer and0.1 M NaCl at 37° C. in a standard USP 2 rotating paddle apparatus withthe paddles spinning at 50 rpm dissolves: (a) not less than 20% of thepalbociclib in 15 minutes; (b) not less than 30% of the palbociclib in30 minutes; (c) not less than 25% of the palbociclib in 60 minutes; or(d) two or more of (a), (b) and (c).

In other embodiments, the invention provides a solid dosage form of anyof the embodiments described herein, wherein the dosage form when addedto a test medium comprising 500 mL of 50 mM pH 6.5 phosphate buffer and0.1 M NaCl at 37° C. in a standard USP 2 rotating paddle apparatus withthe paddles spinning at 50 rpm dissolves: (a) not less than 40% of thepalbociclib in 15 minutes; (b) not less than 35% of the palbociclib in30 minutes; (c) not less than 25% of the palbociclib in 60 minutes; or(d) two or more of (a), (b) and (c).

In a fourth aspect, the invention provides a solid dosage form of any ofthe embodiments described herein, wherein the dosage form: (a) has amean fed/fasted ratio of the area under the plasma concentration versustime curve (AUC) from about 0.8 to about 1.25 after administration of asingle oral dose to a subject; (b) has a mean fed/fasted ratio of themaximum plasma concentration (C_(max)) from about 0.8 to about 1.25after administration of a single oral dose to a subject; or (c) both (a)and (b).

In a fifth aspect, the invention provides a solid dosage form of any ofthe embodiments described herein, wherein the dosage form: (a) providesa mean fasted AUC in the range of 80% to 125% of the mean fasted AUC fora control immediate release (IR) oral capsule containing an equivalentamount of palbociclib after administration of a single oral dose to asubject; or (b) provides a mean fasted C_(max) in the range of 80% to125% of the mean fasted C_(max) for a control immediate release (IR)oral capsule containing an equivalent amount of palbociclib afteradministration of a single oral dose to a subject; or (c) both (a) and(b).

In a sixth aspect, the invention provides a solid dosage form of any ofthe embodiments described herein, wherein the dosage form: (a) providesa mean AUC in the presence of a proton pump inhibitor (PPI) in the rangeof 80% to 125% of the mean AUC in the absence of the PPI afteradministration of a single oral dose to a subject; (b) provides a meanC_(max) in the presence of a proton pump inhibitor (PPI) in the range of80% to 125% of the mean C_(max) in the absence of the PPI afteradministration of a single oral dose to a subject; or (c) both (a) and(b). In some such embodiments, the PPI is rabeprazole.

In a seventh aspect, the invention provides a solid dosage form of anyof the embodiments described herein, wherein the dosage form exhibitsless than 0.3% acid adduct by weight after storage for 96 days at 30° C.and 75% relative humidity (RH).

In an eighth aspect, the invention provides a solid dosage form of anyof the embodiments described herein, wherein the dosage form exhibitsless than 1.0% acid adduct by weight after storage for 2 years at 30° C.and 75% RH.

In a ninth aspect, the invention provides a solid dosage form of any ofthe embodiments described herein, wherein the dosage form exhibits lessthan 0.05% acid adduct by weight after storage for 1 year at 25° C./60%RH. In some such embodiments, the dosage form is packaged with adesiccant canister in a bottle using a heat-induction seal.

In some embodiments of each of the aspects of the invention, the activepharmaceutical ingredient (API), palbociclib, comprises from about 10%to about 35% of the dosage form by weight. In specific embodiments,palbociclib comprises about 20% of the dosage form by weight.

In some embodiments of each of the aspects of the invention, thewater-soluble acid comprises from about 5% to about 40% of the dosageform by weight. In particular embodiments, the water-soluble acidcomprises from about 5% to about 25% of the dosage form by weight. Inother embodiments, the water-soluble acid comprises from about 5% toabout 15% of the dosage form by weight. In more particular embodiments,the water-soluble acid comprises about 10% of the dosage form by weight.

In some such embodiments, the water-soluble acid is selected from thegroup consisting of succinic acid, malic acid and tartaric acid. Inspecific embodiments, the water-soluble acid is succinic acid. In otherembodiments, the water-soluble acid is malic acid. In furtherembodiments, the water-soluble acid is tartaric acid.

In a preferred embodiment of each of the aspects described herein, thesolid dosage form comprises from about 10 wt % to about 35 wt % ofpalbociclib, from about 5 wt % to about 25 wt % of a water-soluble acidselected from the group consisting of succinic acid, malic acid andtartaric acid, and a pharmaceutically acceptable carrier. In particularembodiments, the water-soluble acid is succinic acid. In some suchembodiments, the solid dosage form comprises about 20 wt % ofpalbociclib, about 10 wt % of succinic acid, and a pharmaceuticallyacceptable carrier.

In some embodiments of each of the aspects described herein, thepharmaceutically acceptable carrier comprises one or more of thefollowing pharmaceutically acceptable excipients: diluents,disintegrants, binders, lubricants, glidants and surface-active agents.Such excipients may be incorporated into tablet forms eitherintragranularly or extragranularly, and tablets may comprise the same ordifferent excipients as intragranular or extragranular components. Forexample, a tablet formulation may comprise an intragranular lubricant,an extragranular lubricant, or both an intragranular and anextragranular lubricant which may be the same or different.

In some embodiments of each of the aspects described herein, thepharmaceutically acceptable carrier comprises at least one diluent,wherein the diluent comprises about 50 wt % to about 75 wt % of thesolid dosage form. In certain embodiments, the carrier comprises atleast one diluent selected from the group consisting of microcrystallinecellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesiumcarbonate, dibasic calcium phosphate and tribasic calcium phosphate. Inspecific embodiments, the diluent is microcrystalline cellulose. In somesuch embodiments, the diluent is microcrystalline cellulose.

In other embodiments of each of the aspects described herein, thepharmaceutically acceptable carrier comprises a lubricant, wherein thelubricant comprises from about 0.5 wt % to about 10 wt % of the soliddosage form. In certain embodiments, the carrier comprises at least onelubricant selected from the group consisting of magnesium stearate,calcium stearate, zinc stearate, and sodium stearyl fumarate. Inspecific embodiments, the lubricant is magnesium stearate, which may beincluded intragranularly, extragranularly, or both. In otherembodiments, the lubricant is sodium stearyl fumarate. Other embodimentscomprise both magnesium stearate and sodium stearyl fumarate aslubricants, which may be included intragranularly, extragranularly, orboth.

In further embodiments of each of the aspects described herein, thepharmaceutically acceptable carrier comprises at least one disintegrant,wherein the disintegrant comprises from about 5 wt % to about 10 wt % ofthe solid dosage form. In certain embodiments, the carrier comprises atleast one disintegrant selected from the group consisting ofcrospovidone, croscarmellose sodium and sodium starch glycolate. Inspecific embodiments, the disintegrant is crospovidone.

In frequent embodiments of each of the aspects described herein, thesolid dosage form of the invention is in the form of a tablet. In someembodiments, the tablet is film coated. In some embodiments, the tabletis a monolayer tablet. In other embodiments, the tablet is a bilayertablet. In particular embodiments, the tablets of the invention comprisepalbociclib in the amount of 25 mg, 75 mg, 100 mg or 125 mg. In specificembodiments, the tablets of the invention comprise palbociclib in theamount of 125 mg.

The frequent embodiments of each of the aspects of the invention, thesolid dosage form is in the form of a tablet. In some embodiments, thetablet is a monolayer tablet. In other embodiments, the tablet is abilayer tablet.

In some embodiments of the aspects and embodiments described herein, theamount of palbociclib in the dosage form is 25 mg, 75 mg, 100 mg or 125mg. In specific embodiments, the amount of palbociclib in the dosageform is 125 mg.

Each of the embodiments of the present invention described herein may becombined with one or more other embodiments of the present inventiondescribed herein that are not inconsistent with the embodiment(s) withwhich it is combined.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. In vitro dissolution data for prototype formulations comprisingeight test water soluble acids (malic, maleic, succinic, fumaric,tartaric, tosylic, benzoic and benzenesulfonic acids) at 37° C. in a pH5.5, 10 mM sodium acetate buffer solution in a USP 2 apparatus withpaddles spinning at 50 rpm.

FIG. 2. In vitro dissolution data for prototype formulations comprisingsuccinic acid, malic acid and tartaric acid at 37° C. in a pH 5.5, 10 mMsodium acetate buffer solution in a USP 2 apparatus with paddlesspinning at 50 rpm.

FIG. 3. Non-sink in vitro dissolution data for prototype formulationscomprising succinic acid at 37° C. in a pH 6.5, 50 mM phosphate buffersolution containing+0.1 M NaCl, in a USP 2 apparatus with paddlesspinning at 50 rpm.

FIG. 4. Non-sink in vitro dissolution data for formulations A1, A2 and Bat 37° C. in a pH 6.5, 50 mM phosphate buffer solution containing+0.1 MNaCl, in a USP 2 apparatus with paddles spinning at 50 rpm.

DETAILED DESCRIPTION OF THE INVENTION

The present invention may be understood more readily by reference to thefollowing detailed description of the preferred embodiments of theinvention and the Examples included herein. It is to be understood thatthe terminology used herein is for the purpose of describing specificembodiments only and is not intended to be limiting. It is further to beunderstood that unless specifically defined herein, the terminology usedherein is to be given its traditional meaning as known in the relevantart.

As used herein, the singular form “a”, “an”, and “the” include pluralreferences unless indicated otherwise. For example, “an” excipientincludes one or more excipients.

The term “about” means having a value falling within an acceptedstandard of error of the mean when considered by one of ordinary skillin the art. Frequently, the term “about” refers to ±15%, preferably±10%, and more preferably ±5% of the value or range to which it refers.For example, “about 10 wt %” means 10 wt %±1.5 wt %, preferably 10 wt%±1 wt %, and more preferably 10 wt %±0.5 wt %.

Unless otherwise indicated herein, palbociclib refers the free base formof6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one,which may be present in crystalline or amorphous form, or a mixture ofamorphous and crystalline forms.

The absorption of orally administered drugs may be affected by changesin pH as the drug passes through the gastrointestinal (GI) tract.Absorption may occur at different locations along the GI tract, e.g., atthe cheek lining, or in the stomach, duodenum, jejunum, ileum or colon.The pH differs at each site of absorption, with the pH of the stomach(pH 1-3.5) differing significantly from the pH of the small intestine(pH 4.5-8). Drugs having pH-dependent solubility may precipitate fromsolution as the drug passes through the GI tract, resulting in inter- orintra-patient variability in the extent and/or rate of absorptionbetween doses or patients.

The pH of the GI tract may also vary based on whether a patient orsubject is in a fed or fasted state. In general, the gastric residencetime of a drug is longer in the presence of food than in the fastedstate. If the bioavailability of a drug is significantly affected by thepresence or absence of food in the GI tract, the drug is said to exhibita “food effect”. The rate of gastric emptying may also influence theconcentration of drug in solution available for absorption at differentsites along the GI tract.

Co-administration of certain medications, as well as medical conditionssuch as achlorhydria, may also affect the pH of the GI tract. The use ofacid-reducing agents, such as proton pump inhibitors (PPIs) or H2receptor antagonists, may result in a relatively high stomach pH, whichcan result in only partial dissolution of drugs having pH-dependentsolubility in the stomach. Further dissolution of the undissolved drugmay be inhibited by low solubility in the higher pH environment of theupper intestine. This can result in non-uniform dissolution of drugshaving pH-dependent solubility, increasing the risk of drug-druginteractions, and potentially leading to decreased absorption andreduced therapeutic benefit.

A study in healthy volunteers showed that exposure with palbociclibtreatment (125 mg administered once daily as a free base capsule) wasmarginally increased in fed (AUCinf, 23%-27%; C max, 21%-24%) versusfasted (AUCinf, 39%; C max, 73%) subjects, and PK variability wasgreatly reduced in the fed state. Ruiz-Garcia et al., Annals of Oncology(2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331. Because of thereduced inter-patient variability observed in the fed state, it isrecommended on the U.S. package insert that commercial free basecapsules of palbociclib be taken with food.

When formulating a compound into a tablet or other solid dosage form, itis desirable to develop a formulation which is storage stable attemperatures and relative humidity levels above those typicallyencountered. Other desirable properties in a formulation may also besought, such as fast dissolution so that the tablet quickly dissolvesand the drug is available for absorption. Accordingly, good storagestability and fast dissolution were, inter alia, features that weresought as desirable characteristics for the instant invention.

Drug dissolution represents a critical factor affecting the rate ofsystemic absorption. A variety of in vitro methods have been developedfor assessing the dissolution properties of pharmaceutical formulations,and dissolution testing is sometimes used as a surrogate for the directevaluation of drug bioavailability. See, e.g., Emmanuel et al.,Pharmaceutics (2010), 2:351-363, and references cited therein.Dissolution testing measures the percentage of the API that has beenreleased from the drug product (i.e., tablet or capsule) and dissolvedin the dissolution medium under controlled testing conditions over adefined period of time. To maintain sink conditions, the saturationsolubility of the drug in the dissolution media should be at least threetimes the drug concentration. For low solubility compounds, dissolutionmay sometimes be determined under non-sink conditions. Dissolution isaffected by the properties of the API (e.g., particle size, crystalform, bulk density), the composition of the drug product (e.g., drugloading, excipients), the manufacturing process (e.g., compressionforces) and the stability under storage conditions (e.g., temperature,humidity).

Methods for assessing the chemical storage stability of solid dosageforms under accelerated aging conditions have been described in theliterature. See, e.g., S. T. Colgan, T. J. Watson, R. D. Whipple, R.Nosal, J. V. Beaman, D. De Antonis, “The Application of Science and RiskBased Concepts to Drug Substance Stability Strategies” J. Pharm. Innov.7:205-2013 (2012); Waterman K C, Carella A J, Gumkowski M J, et al.Improved protocol and data analysis for accelerated shelf-lifeestimation of solid dosage forms. Pharm Res 2007; 24(4):780-90; and S.T. Colgan, R. J. Timpano, D. Diaz, M. Roberts, R. Weaver, K. Ryan, K.Fields, G. Scrivens, “Opportunities for Lean Stability Strategies” J.Pharm. Innov. 9:259-271 (2014).

For the solid dosage forms of the present invention, the formation of anacid adduct of the piperazinyl moiety of palbociclib and thewater-soluble acid is a key degradant that is monitored to assessstorage stability.

As further described herein, the present invention provides solid dosageforms comprising palbociclib, a water-soluble acid, and apharmaceutically acceptable carrier, and methods for their productionand use.

Solid dosage forms include, but are not limited to, immediate releasetablets and capsules, controlled-release (CR) tablets and capsules,fast-dissolve dosage forms, chewable dosage forms, sachets, etc.Preferably, the dosage form of the present invention is in the form of atablet, including monolayer or bilayer tablets.

A “solid dosage form” of the present invention is apharmaceutically-acceptable solid dosage form that is safe for oraladministration to humans, where all excipients in the dosage form arepharmaceutically acceptable for use in oral formulations, in other wordssafe for human ingestion. In frequent embodiments, the solid dosage formis a tablet.

As used herein, the term “unit dose” or “unit dosage” refers to aphysically discrete unit that contains a predetermined quantity ofactive ingredient calculated to produce a desired therapeutic effect.The unit dose or unit dosage may be in the form of a tablet, capsule,sachet, etc. referred to herein as a “unit dosage form.”

The term “fasted” as used herein is defined as follows: the dosing statewhich is defined following an overnight fast (wherein 0 caloric intakehas occurred) of at least 10 hours (i.e., 0 hours). Subjects mayadminister the dosage form with 240 mL of water. No food should beallowed for at least 4 hours post-dose. Water may be allowed as desiredexcept for one hour before and after drug administration.

The term “fed” as used herein is defined as follows: the dosing statewhich is defined following an overnight fast (wherein 0 caloric intakehas occurred) of at least 10 hours, subjects then begin the recommendedmeal. Subjects should eat this meal in 30 minutes or less; however thedrug product should be administered 30 minutes after the start of themeal. The drug product may be administered with 240 mL of water. No foodshould be allowed for at least 4 hours post-dose. Water may be allowedas desired except for one hour before and after drug administration.

To assess the fed/fasted ratio, a single oral dose of palbociclib may beadministered: 30 minutes after a high-fat, high-calorie meal (˜800-1000calories with 150, 250, and 500-600 calories from protein, carbohydrate,and fat, respectively); 30 minutes after a low-fat, low-calorie meal(˜400-500 calories with 120, 250, and 28-35 calories from protein,carbohydrate, and fat, respectively); or between meals (1 hour after/2hours before) for a moderate fat and calorie content meal (˜500-700calories consisting of 15% protein, 50% carbohydrate, and 35% fat).

A high fat and high calorie meal may be used as the test meal under thefed condition. An example high fat test meal would be two eggs fried inbutter, two strips of bacon, two slices of toast with butter, fourounces of hash brown potatoes and eight ounces of whole milk.

The calculation of the mean area under the serum concentration versustime curve (AUC) is a well-known procedure in the pharmaceutical artsand is described, for example, in Welling, “Pharmacokinetics Processesand Mathematics,” ACS Monograph 185 (1986). AUC as used herein includesarea under the concentration-time curve from time zero extrapolated toinfinite time following a single dose or the area under theconcentration-time curve from time zero to time of the end of dosinginterval following steady state/multiple doses.

In addition, the calculations for C_(max), C_(min,ss), T_(max), andelimination half-life (t ½), are also known to this of ordinary skill inthe art and is described, for example, in Shargel, Wu-Pong, and Yu,Applied Biopharmaceutics and Pharmacokinetics (2005).

To determine the mean fed/fasted ratio, the individual ratio of the meanarea under the plasma concentration versus time curve of palbociclib(e.g. AUC_(0-inf)) in the fed state to the mean area under the plasmaconcentration versus time curve of palbociclib (e.g. AUC_(0-inf)) in thefasted state is first calculated, and then the corresponding individualratios are averaged together. In this way, it is the average of eachcorresponding individual's ratio which is determined.

Proton-pump inhibitors (PPIs) are a well-known class of drugs thatreduce the production of gastric acid, thereby modifying gastric pH.Representative PPIs include, for example, rabeprazole, omeprazole(including S- and B-forms, Na and Mg salts), lansoprazole, pantoprazole,esomeprazole, and the like.

As used herein, the term “control immediate release (IR) oral capsule”refers to the commercial IR capsule formulation of palbociclib asdescribed in Example 11. This formulation, along with an isethionatesalt formulation (ISE) and a free base tablet dosage form that lacks thewater-soluble acid but is otherwise substantially the same as theformulation in Example 1 may be referenced herein as controls.

“Dissolution Test 1” refers to the following test of dosage forms ofpalbociclib. The dissolution test is conducted in a standard USP 2rotating paddle apparatus as disclosed in United States Pharmacopoeia(USP) Dissolution Test Chapter 711, Apparatus 2. Paddles are rotated at50 rpm and the dosage form is added to 500 mL of 10 mM pH 5.5 acetatebuffer at 37° C. At appropriate times following test initiation (e.g.,insertion of the dosage form into the apparatus), filtered aliquots(typically 1.5 mL) from the test medium are analyzed for palbociclib byhigh performance liquid chromatography (HPLC). Dissolution results arereported as the percent of the total dose of palbociclib testeddissolved versus time.

“Dissolution Test 2” refers to the following test of dosage forms ofpalbociclib. The dissolution test is conducted in a standard USP 2rotating paddle apparatus as disclosed in United States Pharmacopoeia(USP) Dissolution Test Chapter 711, Apparatus 2. Paddles are rotated at50 rpm and the dosage form is added to 500 mL of 50 mM pH 6.5 phosphatebuffer and 0.1 M NaCl at 37° C. At appropriate times following testinitiation (e.g., insertion of the dosage form into the apparatus),filtered aliquots (typically 1.5 mL) from the test medium are analyzedfor palbociclib by high performance liquid chromatography (HPLC).Dissolution results are reported as the percent of the total dose ofpalbociclib tested dissolved versus time.

The term “dry granulation” means the process of blending bulk activeproduct with at least one excipient. The blend is then compressed, orcompacted, to form a compressed material or “compact”. This material maybe broken apart to form granules by crushing, grinding or cutting intodry granulated particles. Optionally, the particles may be furtherprocessed. Crushing, grinding, or cutting processes involve an operationthat reduces the size of the compressed material such as accomplished bymilling or by other operations known to those skilled in the art.

The term “water-soluble” used herein in relation to the acid present inthe composition refers to an acid that has a solubility of at least 0.2%by weight in water at 25° C. The water-soluble acid may be an organic orinorganic acid, and preferably is an organic acid having at least onepKa value which is at least one (preferably at least two) pK unit lowerthan the highest pKa of the basic groups present in the drug. In thecase of the palbociclib, which has pKa values of approximately 4.1 and7.3, the acid preferably has a pKa of less than 6.3, and more preferablya pKa of less than 5.3. Water-soluble organic acids include, forexample, C₂-C₈ or C₂-C₆ aliphatic mono or poly-carboxylic acids, andpreferably C₄-C₆ aliphatic mono or poly-carboxylic acids. Particularlypreferred are C₄-C₆ dicarboxylic acids, which may be saturated orunsaturated.

Solid dosage forms of the invention may comprise a single water-solubleacid, or may include a combination of two or more such acids. Inselected embodiments of the invention, the water-soluble acid isselected from the group consisting of succinic acid, malic acid andtartaric acid. In certain preferred embodiments of the invention, thewater-soluble acid is succinic acid.

The water-soluble acid may be combined with the drug prior togranulation or it may be incorporated into the dosage form along withextragranular excipients. In a bilayer tablet, the water-soluble acidmay be present in the active layer containing palbociclib, incorporatedinto a separate acid layer, or water-soluble acids (which may be thesame or different) may be incorporated into both the active and acidlayers.

Without wishing to be bound by theory, it is thought that the presenceof an acid in the solid dosage form in close contact with the drugincreases solubilization by way of an interaction between palbocicliband the acid. The solid dosage forms of the invention thereby provide anincreased local concentration of the drug in solution following oraladministration to a subject as compared to administration of palbociclibformulations lacking the water-soluble acid.

In some embodiments, the solid dosage form of any of the embodimentsdescribed herein, under the conditions of Dissolution Test 1 (pH 5.5acetate buffer, 37° C.), dissolves: (a) not less than 35% of thepalbociclib in 15 minutes; (b) not less than 45% of the palbociclib in30 minutes; (c) not less than 55% in 60 minutes; or (d) two or more of(a), (b) and (c).

In further embodiments, the solid dosage form of the invention under theconditions of Dissolution Test 1 dissolves: (a) not less than 25%, 30%,35%, 40%, 45%, or 50%, or more than 50% of the palbociclib is dissolvedin 15 minutes; (b) not less than 35%, 40%, 45%, 50%, 55%, or 60%, ormore than 60% of the palbociclib is dissolved in 30 minutes; and/or (c)not less than 45%, 50%, 55%, 60%, 65%, or 70% or more than 70% of thepalbociclib is dissolved in 60 minutes.

In some embodiments, the solid dosage form of any of the embodimentsdescribed herein, under the non-sink conditions of Dissolution Test 2(pH 6.5 phosphate buffer and 0.1 M NaCl, 37° C.) dissolves: (a) not lessthan 40% of the palbociclib in 15 minutes; (b) not less than 35% of thepalbociclib in 30 minutes; (c) not less than 25% of the palbociclib in60 minutes; or (d) two or more of (a), (b) and (c).

In other embodiments, the solid dosage form of any of the embodimentsdescribed herein, under the non-sink conditions of Dissolution Test 2(pH 6.5 phosphate buffer and 0.1 M NaCl, 37° C.) dissolves: (a) not lessthan 15% of the palbociclib in 15 minutes; (b) not less than 20% of thepalbociclib in 30 minutes; (c) not less than 25% of the palbociclib in60 minutes; or (d) two or more of (a), (b) and (c).

In other embodiments under Dissolution Test 2: (a) not less than 10%,15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, or more than 50% of thepalbociclib is dissolved in 15 minutes; (b) not less than 15%, 20%, 25%,30%, 35%, 40%, 45%, or 50%, or more than 50% of the palbociclib isdissolved in 30 minutes; and/or (c) not less than 15%, 20%, 25%, 30%,35%, or 40%, or more than 40% of the palbociclib is dissolved in 60minutes.

In further embodiments under Dissolution Test 2: (a) not less than 30%,35%, 40%, 45%, or 50%, or more than 50% of the palbociclib is dissolvedin 15 minutes; (b) not less than 25%, 30%, 35%, 40%, 45%, or 50%, ormore than 50% of the palbociclib is dissolved in 30 minutes; and/or (c)not less than 15%, 20%, 25%, 30%, 35%, or 40%, or more than 40% of thepalbociclib is dissolved in 60 minutes.

In some embodiments, the invention provides a solid dosage formcomprising palbociclib, a water-soluble acid, and a pharmaceuticallyacceptable carrier, wherein the dosage form provides: (a) a meanfed/fasted ratio of the area under the plasma concentration versus timecurve (AUC) from about 0.8 to about 1.25 after administration of asingle oral dose to a subject; (b) a mean fed/fasted ratio of themaximum plasma concentration (C_(max)) from about 0.8 to about 1.25after administration of a single oral dose to a subject; or (c) both (a)and (b).

In some embodiments, the invention provides a solid dosage formcomprising palbociclib, a water-soluble acid, and a pharmaceuticallyacceptable carrier, wherein the dosage form provides: (a) a mean fastedAUC in the range of 80% to 125% of the mean fasted AUC for a controlimmediate release (IR) oral capsule containing an equivalent amount ofpalbociclib after administration of a single oral dose to a subject; (b)a mean fasted C_(max) in the range of 80% to 125% of the mean fastedC_(max) for a control immediate release (IR) oral capsule containing anequivalent amount of palbociclib after administration of a single oraldose to a subject; or (c) both (a) and (b).

In further embodiments, the invention provides a solid dosage formcomprising palbociclib, a water-soluble acid, and a pharmaceuticallyacceptable carrier, wherein the dosage form provides: (a) a mean AUC inthe presence of a proton pump inhibitor (PPI), preferably rabeprazole,in the range of 80% to 125% of the mean AUC in the absence of the PPIafter administration of a single oral dose to a subject; (b) a meanC_(max) in the presence of a proton pump inhibitor (PPI), preferablyrabeprazole, in the range of 80% to 125% of the mean C_(max) in theabsence of the PPI after administration of a single oral dose to asubject; or (c) both (a) and (b).

In other embodiments, the invention provides a solid dosage formcomprising palbociclib, a water-soluble acid, and a pharmaceuticallyacceptable carrier, wherein the dosage form exhibits less than 0.4%,0.35%, 0.3%, 0.25%, 0.2%, 0.15% or 0.1% acid adduct by weight afterstorage for 96 days at 30° C. and 75% relative humidity (RH).

In still other embodiments, the invention provides a solid dosage formcomprising palbociclib, a water-soluble acid, and a pharmaceuticallyacceptable carrier, wherein the dosage form exhibits less than 1.5%,1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4% or 0.3%acid adduct by weight after storage for 2 years at 30° C. and 75% RH.

In some embodiments of each of the aspects and embodiments of theinvention, the water-soluble acid is selected from the group consistingof succinic acid, malic acid and tartaric acid. In specific embodimentsof each of the aspects and embodiments herein, the water-soluble acid issuccinic acid. In other embodiments, the water-soluble acid is malicacid. In further embodiments, the water-soluble acid is tartaric acid.

In some embodiments of each of the aspects of the invention, thewater-soluble acid comprises from about 5% to about 40% of the dosageform by weight. In particular embodiments, the water-soluble acidcomprises from about 5% to about 25% of the dosage form by weight. Insome embodiments, the water-soluble acid comprises about 5%, 10%, 15%,20%, 25%, 30%, 35% or 40% of the dosage form by weight.

In some embodiments of each of the aspects of the invention, palbociclibcomprises from about 10% to about 35% of the dosage form by weight. Inspecific embodiments, palbociclib comprises about 20% of the dosage formby weight. In some embodiments, the palbociclib comprises about 5%, 10%,15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of the dosage form by weight.

In frequent embodiments of each of the aspects and embodiments herein,the solid dosage form is a tablet, preferably a tablet formed bydry-granulation. In some such embodiments, the tablet is a bilayertablet. In particular embodiments, the bilayer tablet comprises: (a) anactive layer comprising palbociclib and a pharmaceutically acceptablecarrier; and (b) an acid layer comprising a water-soluble acid and apharmaceutically acceptable carrier. In some embodiments, the bilayertablet comprises: (a) an active layer comprising palbociclib, awater-soluble acid, and a pharmaceutically acceptable carrier; and (b)an acid layer comprising a water-soluble acid and a pharmaceuticallyacceptable carrier, wherein the water-soluble acid in the active layermay be the same or different than the water-soluble acid in the acidlayer. In a specific embodiment, the water-soluble acid in the activelayer is succinic acid and the water-soluble acid in the acid layer istartaric acid.

In another aspect, the invention provides a method of treating cancercomprising administering to a subject in need thereof a therapeuticallyeffective amount of the solid dosage form of any of the aspects andembodiments described herein. In particular embodiments, the cancer isbreast cancer. In some such embodiments, the breast cancer ishormone-receptor positive (HR+) breast cancer. In some such embodiments,the breast cancer is estrogen-receptor positive (ER+) breast cancer. Insome such embodiments, the breast cancer is human epidermal growthfactor receptor 2 negative (HER−) breast cancer. In other suchembodiments, the breast cancer is human epidermal growth factor receptor2 positive (HER+) breast cancer. In further embodiments, the breastcancer is advanced or metastatic breast cancer, which may becharacterized as HR+, HER2− or ER+, HER2−.

Palbociclib may be administered alone or in combination with otherdrugs, in particular aromatase inhibitors, e.g., letrozole, fulvestrantor exemestane, and will generally be administered as a formulation inassociation with one or more pharmaceutically acceptable excipients. Theterm “excipient” describes any ingredient other than palbociclib or asalt thereof.

Palbociclib may be administered orally. Oral administration may involveswallowing, so that the compound enters the gastrointestinal tract, orbuccal or sublingual administration may be employed by which thecompound enters the blood stream directly from the mouth.

A therapeutically effective amount of dosage form of the invention maybe administered to a subject in need of such treatment. The term“therapeutically effective amount” as used herein refers to that amountof a compound being administered which will relieve to some extent oneor more of the symptoms of the disorder being treated. In reference tothe treatment of cancer, a therapeutically effective amount refers tothat amount which has the effect of (1) reducing the size of the tumor,(2) inhibiting (that is, slowing to some extent, preferably stopping)tumor metastasis, (3) inhibiting to some extent (that is, slowing tosome extent, preferably stopping) tumor growth or tumor invasiveness,and/or (4) relieving to some extent (or, preferably, eliminating) one ormore signs or symptoms associated with the cancer.

As used herein, “subject” refers to a human or animal subject. Incertain preferred embodiments, the subject is a human. In someembodiments, the subject is a patient afflicted with a disease state. Inother embodiments, the subject may be a healthy volunteer.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating asdefined immediately above. The term “treating” also includes adjuvantand neo-adjuvant treatment of a subject. Palbociclib may be administeredalone, or in combination with an aromatase inhibitor, such as letrozole,fulvestrant or exemestane.

As used herein “cancer” refers to any malignant and/or invasive growthor tumor caused by abnormal cell growth. As used herein “cancer” refersto solid tumors named for the type of cells that form them (e.g., breastcancer), and cancers of blood, bone marrow, or the lymphatic system.Examples of solid tumors include but not limited to sarcomas andcarcinomas. Examples of cancers of the blood include but not limited toleukemias, lymphomas and myeloma. The term “cancer” includes but is notlimited to a primary cancer that originates at a specific site in thebody, a metastatic cancer that has spread from the place in which itstarted to other parts of the body, a recurrence from the originalprimary cancer after remission, and a second primary cancer that is anew primary cancer in a person with a history of previous cancer ofdifferent type from latter one.

More specifically, examples of cancer in connection with the presentinvention include, inter alia, breast cancer, preferably in combinationwith an aromatase inhibitor. For example, the cancer may be hormonereceptor positive (HR+) breast cancer, and in particular estrogenreceptor positive (ER+) breast cancer. In some embodiments, said ER+breast cancer is human epidermal growth factor 2 (HER2)-negative. Infurther embodiments, the cancer is ER+, HER2− advanced metastatic breastcancer, wherein the drug is administered in combination with anaromatase inhibitor for treatment of metastatic disease.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules, powders, lozenges (including liquid-filled),sachets and the like. In a preferred aspect of the invention, the soliddosage form provided herein is a tablet. In some such embodiments, thetablet is film coated. In other such embodiments, the tablet is abilayer tablet.

For tablet dosage forms, depending on dose, palbociclib may make up from1 wt % to 80 wt % of the dosage form, typically from 5 wt % to 60 wt %,more typically from about 10 wt % to about 35 wt %, or even moretypically from about 15 wt % to about 25 wt % of the dosage form. Inspecific embodiments, palbociclib comprises about 20 wt % of the dosageform by weight.

In the solid dosage forms of the invention, the carrier may comprise avariety of pharmaceutically acceptable excipients, including, forexample, diluents, disintegrants, binders, lubricants, glidants andsurface-active agents. Formulations may also include excipients such aspreservatives, anti-oxidants, flavors and colorants, as well as otherexcipients known in the art.

Solid dosage forms, such as tablets, typically contain diluents, e.g.,lactose (monohydrate, spray-dried monohydrate, anhydrous and the like),mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar,microcrystalline cellulose, powdered cellulose, starch, pregelatinizedstarch, dextrates, dextran, dextrin, dextrose, maltodextrin, calciumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate,calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers,polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.Different types of microcrystalline cellulose may be suitable for use inthe formulations described herein. Examples of microcrystallinecellulose include Avicel® types: PH101, PH102, PH103, PH105, PH 112,PH113, PH200, PH301, and other types of microcrystalline cellulose, suchas silicified microcrystalline cellulose (SMCC). In some embodiments,the diluent is selected from the group consisting of microcrystallinecellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesiumcarbonate, dibasic calcium phosphate, tribasic calcium phosphate, ormixtures thereof. In certain embodiments, the diluent comprisesmicrocrystalline cellulose. In some embodiments, the diluent comprisesone or more types of microcrystalline cellulose, for example Avicel®PH105, Avicel® PH200 or mixtures thereof. In some such embodiments, thediluent excludes lactose monohydrate. In other such embodiments, thediluent comprises microcrystalline cellulose and further compriseslactose monohydrate. Diluents frequently comprise from about 25 wt % toabout 75 wt % of the solid dosage form, and preferably from about 50 wt% to about 75 wt % of the dosage form.

Solid dosage forms frequently contain disintegrants. Examples ofdisintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, croscarmellose sodium,crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystallinecellulose, lower alkyl-substituted hydroxypropyl cellulose, starch,pregelatinized starch, and sodium alginate. In some embodiments, thedisintegrant is crospovidone. Any grade of crospovidone can be used; forexample CL, CL-SF and XL grades of crospovidone are suitable for use inthe formulations described herein. Specific examples include Kollidon,Kollidon CL®, Kollidon CL-M®, Polyplasdone XL®, Polyplasdone XL-10®, andPolyplasdone INF-10®. In some embodiments, the carrier comprises atleast one disintegrant selected from the group consisting ofcrospovidone, croscarmellose sodium and sodium starch glycolate. Inspecific embodiments, the disintegrant is crospovidone. Disintegrantsfrequently comprise from about 1 wt % to about 25 wt %, preferably fromabout 5 wt % to about 20 wt %, more preferably from about 5 wt % toabout 10 wt % of the dosage form.

Binders may be used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose,and hydroxypropyl methylcellulose. In some embodiments, the binder isselected from the group consisting of microcrystalline cellulose,hydroxypropyl cellulose and hydroxypropyl methylcellulose. In specificembodiments, the binder is microcrystalline cellulose, e.g. Avicel®PH105. When present, binders may comprise from about 0 wt % to about 15wt %, or from about 0.2 wt % to about 10 wt % of the dosage form. Insome embodiments, the binder comprises about 5 wt % to about 10 wt % ofthe dosage form. In particular embodiments, the binder comprises about10 wt % of the dosage form.

Solid dosage forms frequently contain one or more lubricants. Examplesof lubricants include magnesium stearate, calcium stearate, zincstearate, sodium stearyl fumarate, mixtures of magnesium stearate withsodium lauryl sulfate, or mixtures of two or more of these. In someembodiments, the lubricant is magnesium stearate and/or sodium stearylfumarate. In some embodiments, the lubricant is magnesium stearate. Insome such embodiments, the solid dosage form is a tablet comprisingintragranular and extragranular magnesium stearate. In otherembodiments, the solid dosage form is a tablet comprising intragranularmagnesium stearate and extragranular sodium stearyl fumarate. Whenpresent, lubricants frequently comprise from about 0.25 wt % to about 10wt %, preferably from about 0.5 wt % to about 6 wt % of the dosage form.

Tablets may also compromise glidants, for example silicon dioxide,colloidal silicon dioxide, magnesium silicate, magnesium trisilicate,talc, and other forms of silicon dioxide, such as aggregated silicatesand hydrated silica. In some embodiments, the glidant is silicondioxide. When present, glidants may comprise from about 0 wt % to about10 wt %, preferably from about 0.2 wt % to about 5 wt %, or from about0.5 wt % to about 2 wt % of the tablet.

Tablets may optionally include surface-active agents, such as sodiumlauryl sulfate and polysorbate 80. When present, surface-active agentsmay comprise from 0 wt % to 10 wt %, or preferably 0.2 wt % to 5 wt % ofthe tablet.

In general, the solid dosage forms of the invention are preparedaccording to methods usual in pharmaceutical chemistry. Selectedexcipients may be incorporated along with the API into either or both ofthe extragranular or intragranular compartments.

Exemplary tablet formulations contain from about 10 wt % to about 35 wt% palbociclib, typically from about 15 wt % to about 25 wt %palbociclib; from about 5 wt % to about 15 wt % water-soluble acid; fromabout 25 wt % to about 75 wt % diluent; from about 5 wt % to about 10 wt% disintegrant; from about 0.5 wt % to about 6 wt % lubricant; andoptionally from about 0 wt % to about 5 wt % glidant, and from about 0wt % to about 15 wt % binder.

Further exemplary tablet formulations contain about 20 wt % palbociclib;about 10 wt % water-soluble acid, preferably succinic acid; from about50 wt % to about 75 wt % diluent, preferably microcrystalline cellulose;from about 5 wt % to about 10 wt % disintegrant, preferablycrospovidone; from about 0.5 wt % to about 6 wt % lubricant, preferablymagnesium stearate or sodium stearyl fumarate, or both; optionally fromabout 0 wt % to about 5 wt % glidant; and optionally from about 0 wt %to about 15 wt % binder. When present, the glidant is preferably silicondioxide and the binder is preferably microcrystalline cellulose of anappropriate type (e.g., Avicel® PH105) as a dry binder.

Solid formulations for oral administration may be formulated to beimmediate and/or modified release. Modified release formulations includedelayed-, sustained-, pulsed-, controlled-, targeted-, andprogrammed-release. For a general description of modified releaseformulations, see U.S. Pat. No. 6,106,864.

Pharmaceuticals in the form of solid shaped tablets are typicallymanufactured by compressing the materials that make up the final productinto the desired tablet form. Such materials may include activepharmaceutical ingredients as well as pharmaceutically non-activeexcipients that impart necessary or useful properties to the productduring and after the manufacturing process. Tablet hardness, or tensilestrength can be used as a measure of the cohesiveness of the ingredientsof a tablet. If a tablet does not possess sufficient cohesive propertiesthe tablet may fall apart on handling. The final formulation maycomprise one or more layers and may be coated or uncoated.

As is known in the art, granulation is a process used to improve thehandling and manufacturing properties of a formulation, for example byincreasing particle size to improve flow. Granulation does notsubstantially change the physical form of the drug such as itscrystalline or amorphous character. Various processes are used by thoseof skill in the art for preparing tablet dosage forms. Examples of suchprocesses include dry-granulation, wet-granulation, fluid-bedgranulation and direct compression. The type of method used may dependupon factors such as physical characteristics of the activepharmaceutical ingredients in the formulation, the types of excipientsused and the desired physical characteristics of the final product. Eachof these processes include steps involving mixing of the ingredients ofthe dosage form. In certain embodiments of the present invention,dry-granulation is preferred.

Some amount of mixing of the ingredients of a dosage form is usuallynecessary in order to have a homogeneous and consistent final product.However, in the preparation of pharmaceutical tablets by wet and drygranulation it has been found that the extent and intensity of themixing of the ingredients prior to compression is related to a loss ofcompressibility and cohesiveness of the formulation, resulting inreduced tablet hardness.

A similar result may be observed when roller compaction is used, forexample, in dry granulation methods. Roller compaction may be employedas a method to form the granules that are subsequently compressed intotablets. Roller compaction may reduce the subsequent compressibility andcohesiveness of the dosage form.

Dry granulation is a process in which granulates are formed by acompaction step that is followed by sizing the compacts into particlesthat can be processed easily. It is often used to improve flowproperties and/or densify the formulation which can facilitate furthermanufacturing processes such as tableting, encapsulation and powderfilling. The compacts are made directly from powder blends that usuallycontain an active ingredient and other excipients including a lubricant.

The use of dry granulation techniques may be preferred to wetgranulation methods because of shorter processing times and costadvantages. However, dry granulation is generally limited to thosesituations in which the drug or active ingredient has physicalcharacteristics suitable for forming pharmaceutically acceptablegranulations and dosage forms such as tablets.

The addition of at least one excipient to the formulation is generallyrequired and will contribute to increasing the tablet size of the finalproduct. As tablet size must be within certain parameters to function asa suitable dosage form, there is a limit beyond which increasing tabletsize to accommodate increasing amounts of excipients to enhancecompactability is not practical. As a result, manufacturers are oftenlimited to using the dry granulation method for formulations containinga low dose of the active ingredient per compressed tablet such that theformulation may accommodate sufficient levels of excipient to make drygranulation practical.

In the development of pharmaceutical dosage forms, it is important tobalance several different objectives. It is important to prepare apharmaceutical dosage form as economically as possible. It would bedesirable to have a simple production method comprising a few processingsteps. The dosage form should also optimally make available the activecompound contained therein to the patient. Further, the dosage formshould be easy to swallow. Smaller dosage forms are better accepted bypatients and increase patient compliance.

The final pharmaceutical composition is processed into a unit dosageform (e.g., tablet or capsule) and then packaged for distribution. Theprocessing step will vary depending upon the particular unit dosageform. For example, a tablet is generally compressed under pressure intoa desired shape and a capsule employs a simple fill operation. Thoseskilled in the art are well aware of the procedures used formanufacturing the various unit dosage forms.

Tablets are typically formed by pressure being applied to the materialto be tableted on a tablet press. A formulation must have good flowproperties for precise volumetric feeding of the material to the diecavity and suitable compressibility, compactability, and ejectionproperties to form a tablet.

There are a number of tablet presses, each varying in productivity butsimilar in basic function and operation. All compress a tabletformulation within a die cavity by pressure exerted between two steelpunches, a lower punch and an upper punch. Tablet presses are typicallydesigned to have a hopper for holding and feeding the formulation, afeeding mechanism for feeding the formulation to the die cavity,provision for placement of punches and dies, and in rotary tabletpresses a cam track for guiding the movement of the punches. Two typesof tablet presses are the single station or single-punch press and themultistation rotary press. Some tablet presses provide longer dwelltimes than others, allowing increased bonding to occur. Other pressesmay provide precompression.

Wet granulation methods may also be employed for preparing the granulesof the pharmaceutical composition. Wet granulation methods are describedin Remington: The Science and Practice of Pharmacy, Mack PublishingCompany, Easton, Pa., 19th Edition 1995. These and other methods aregenerally known by those skilled in the art. If wet granulation isemployed, a volatilizable agent may be incorporated in the mixturebefore, during or after mixing of the ingredients, but prior toformation of granules. For example, a solid volatilizable agent can beblended with the powders of the mixture prior to, during or after theaddition of binding agent solutions. Other solid dosage forms may beprepared using techniques including rotary bed granulation orspray-dried dispersion (SDD).

The invention will be illustrated in the following non-limitingexamples.

EXAMPLES Example 1 Free Base Plus Succinic Acid

A tablet comprising the free base form of the API (palbociclib) drygranulated with succinic acid was prepared using the followingprocedure. The tablet had the composition in Table 1.

TABLE 1 Component Amount (mg/tablet) Intragranular componentsPalbociclib (API) 125.000 Succinic Acid 62.500 Microcrystallinecellulose (Avicel PH105) 62.500 Microcrystalline cellulose (AvicelPH102) 196.875 Lactose Monohydrate (Fast Flo 316) 96.875 Crospovidone(Kollidon CL) 31.250 Colloidal silicon dioxide (Aerosil 200 Pharma)6.250 Magnesium Stearate 6.250 Extragranular components Crospovidone31.250 Magnesium Stearate 6.25 TOTAL 625.000

Microcrystalline cellulose (Avicel PH105) was added to a blender (binblender or equivalent) and mixed at low speed for approximately 25revolutions (2 minutes at 12 rpm). The API was added to the blender,rinsing the API container with a portion of the lactose monohydrate, andfolded to mix. The batch quantities of succinic acid, lactosemonohydrate, crospovidone, and colloidal silicon dioxide were added tothe blender which was mixed at low speed for approximately 180revolutions (15 minutes at 12 rpm).

A mill and bag were pre-coated with 50% of the batch quantity ofmicrocrystalline cellulose (Avicel PH102). The blend was passed fromabove through the mill. The mill was flushed with the remaining portionof the microcrystalline cellulose (Avicel PH102), and the milledmaterial transferred from the bag to a blender (bin blender orequivalent) and mixed at low speed for approximately 180 revolutions (15minutes at 12 rpm). The intragranular magnesium stearate was sievedthrough an appropriately sized screen and added to the blender from theprevious step. The mixture was mixed at low speed for approximately 60revolutions (5 minutes at 12 rpm). The blend was Roller compacted(Gerteis Minipactor or equivalent), without separating or recyclingfines. If in-line milling was not employed, the roller compacted blendwas passed through a Comil U5 or U10 equipped with a 1601 impeller, witha screen size of 050G, and a speed of 1000 or 700 rpm, respectively.

The extragranular crospovidone was added to the blender from theprevious step. The mixture was mixed at low speed for approximately 180revolutions (15 minutes at 12 rpm). The extragranular magnesium stearatewas sieved through an appropriately sized screen. It was added to theblender from the previous step, and mixed for approximately 60revolutions (5 minutes at 12 rpm).

To form the tablets, a single station press (Korsch XP 1 or equivalent)or rotary press was used.

Example 2 Bilayer Tablet Formulation

Bilayer tablets containing an active layer and an acid layer wereprepared. The active layer consisted of the granulation blend fromExample 1.

The active and acid layers had the composition in Table 2.

TABLE 2 Component Amount (mg/tablet) Active Layer Granulation Totalaccording to Example 1 625.000 Acid Layer Blend Tartaric acid, granular180.00 Microcrystalline cellulose 143.100 Crospovidone 36.00 MagnesiumStearate 0.900 TOTAL Acid Layer 360.000

The acid layer blend was formed by combining microcrystalline cellulose,tartaric acid and crospovidone into an appropriate sized container. Thecombination was blended for approximately 120 revolutions, and thenpassed through a Comil U5 or U10 equipped with a 1601 impeller, with ascreen size of 018R and a speed of 1000 rpm or 700 rpm, respectively.

The milled material was transferred to a blender and the components werethen blended for approximately 120 revolutions. The magnesium stearatewas sieved through an appropriately sized screen (1 mm screen, US Sieve#20) and then added to the blender, and blended for approximately 50revolutions.

Bilayer tablets were formed using the following procedures using asuitable rotary bilayer tablet press, such as a Korsch XP1. The activelayer granulation, (formed according to the procedures outlined inExample 1) was compressed to a target active layer weight of 625 mg anda recommended active layer thickness of 6.66 mm. The acid layer blendwas added and the acid layer and active layers compressed to the desiredfill weight of 985 mg.

Example 3 Fluid Bed Granulation

The fluid bed coater (a Niro MP-2 Fluid Bed Coater, equipped with a MP-1bowl, with top spray granulation set-up) was pre-heated using thefollowing conditions until the inlet air dew point (12° C.) and productbowl temperatures stabilized (greater than or equal to 45° C.) to thetargets. The spray nozzle was a Schlick 970 with a 0.8 mm liquid tip,and a nozzle to bowl bottom distance of 33 cm.

To form the fluid bed granulation, succinic acid was first milledmanually using a mortar and pestle. Periodically, the milled powder wasplaced on a #60 mesh screen, using manual shaking to pass the materialinto a collection container. The material retained on the screen wasreturned to the mortar and more un-milled material was added. Millingwas continued until the required amount had passed through the screen.

In addition to succinic acid, each of the following dry bed componentsin required amounts were individually screened through a #30 mesh intotheir separate collection containers.

TABLE 3 Component Amount (wt %) Microcrystalline cellulose (AvicelPH102) 37.9 Mannitol 23.3 Succinic Acid 30.0 Crospovidone (PolyplasdoneXL) 8.8 TOTAL 100

The binder suspension was formed by adding water to an appropriatelysized container. Mannitol and hydroxypropyl cellulose were then added tothe container. The solution was mixed for a minimum of 2 hours, and wasvisually free of agglomerations.

The API was then slowly added to the solution to form the bindersuspension. The binder suspension was stirred during processing until itwas used. The binder suspension contained the following components inTable 4:

TABLE 4 Component Amount (wt %) Palbociclib (API) 14.24 Mannitol 2.73Hydroxypropyl Cellulose (Klucel LF) 2.73 Water 80.3 TOTAL 100.0

After the fluid bed product bowl temperature had stabilized, the dry-bedmaterials were then loaded into the fluid bed in the following ordermannitol, microcrystalline cellulose, succinic acid, and crospovidone.

The fluid bed granulation then commenced at a bed temperature of 29-31°C., spray rate of 12-30 g/min, airflow of 70-115 CMH (m³/h) andatomization pressure of 1.1 bar to provide the fluid bed granulation.

Example 4 Fluid Bed Granulation Tablets

Tablets were formed from the fluid bed granulation (FBG) of Example 3,using the following procedures. First, the granulation was dry-sized bypassing the granules through a Comil U5 equipped with a 1601 impeller,with a screen size of 018R, and a speed of 1500 rpm. The granules werefed into the Comil as uniformly as possible by visual assessment (20 to25 minutes for 2 kg granulation). The milled granules were passedthrough a #60 mesh screen, and the material that passes through thescreen was collected in a bag and set aside. Material that was retainedon the #60 mesh screen was milled in a Comil a second time. The milledgranules were passed through a #60 mesh screen, and the materialcollected in a bag. Material retained on the #60 mesh screen after thesecond pass was gently pushed through the screen using a spatula/scraperuntil all had passed through. The material was added to the bag.

The final tablet blend for the FBG tablets is given in Table 5:

TABLE 5 Component Amount (mg/tablet) Intragranular Fluid Bed GranulesFBG according to Example 3 400.0 Extragranular ComponentsMicrocrystalline Cellulose (Avicel PH102) 252.0 Succinic acid 80.0Crospovidone (Polyplasdone XL) 64.0 Magnesium Stearate 4.0 TOTAL 800.0

An adjusted weight of extragranular components was calculated, ifneeded, based on the total weight of milled granules from the previousstep.

The succinic acid was manually milled (with mortar and pestle) in smallaliquots. A sufficient amount was used to ensure the quantity of milledmaterial was sufficient. The milled material was passed through a #60mesh screen and collected in a new bag. Any material retained on thescreen was returned to the mortar with the next aliquot. The requiredamount of milled succinic acid was subdivided.

Next, the microcrystalline cellulose and crospovidone were passedthrough a #30 mesh screen and added to a blender. The milled succinicacid and the dry-sized fluid bed granules were added to an appropriatesized blender. The bulk density was 0.39 g/cc. The mixture was blendedfor 11.25 minutes at 16 rpm (180 revolutions).

Next, the magnesium stearate was combined with 3 to 10 times (volume,estimated visually) of the blend from the previous step in anappropriately sized bottle. The mixture was manually mixed by gentlyshaking for approximately 30 seconds, and then passing through a 30-meshscreen. The contents were added to the blender and blended for 3.75minutes at 16 rpm (60 revolutions).

The batch was compressed to the target specifications using a suitabletablet press, such as a Korsch XM12.

Example 5 Spray Dried Dispersion

A solution of hypromellose (HPMC E3 Prem) was prepared by dissolving3.25 wt % HPMC E3 in a solvent blend of 90/10 methanol/water (w/w) toform a 3.25 wt % HPMC solution. A sufficient quantity of palbociclib(API) was added to this solution to form a spray suspension of thefollowing composition: 1.75 wt % API, 3.25 wt % hypromellose, 85.5 wt %methanol, and 9.5 wt % water. The suspension was then stirredcontinuously to keep the API from settling in the suspension tank.

The spray dryer was preheated using a heated drying gas (nitrogen) at aflow rate of 1850 g/min and at an inlet drying gas temperature of 130°C. Following preheating, a 90/10 (w/w) methanol/water blend was sprayeduntil steady-state thermodynamic conditions were achieved. Once thespray dryer reached steady-state, the spray suspension was thenintroduced into the spray dryer via flash atomization at a feed rate of130 g/min, at a solution temperature of 130° C., and at a pressure of250 psi. A secondary nitrogen gas stream was utilized around the nozzleat a pressure of 60 psi to prevent fouling of the nozzle. The particleswere collected at a temperature of 45° C. at the outlet of the spraydryer.

After collection, the particles were placed into a convection tray dryeroperated at 40° C./15% relative humidity for a minimum of 6 hours. Thisreduced residual solvent in the particles to no more than 0.3 wt %residual methanol).

The particle sizes of the secondary dried particles were measured byMalvern Particle Size Analyzer, available from Malvern Instruments Ltd.of Framingham, Mass., using low dispersive pressures of 0.5 to 1.0 bar,where D(4,3) is the volume mean diameter; DV₁₀ is the diameter thatmakes up 10% of the total volume containing the particles; DV₅₀ is thediameter that makes up 50% of the total volume containing the particles;and DV₉₀ is the diameter that makes up 90% of the total volumecontaining the particles. The particle size is given in Table 6:

TABLE 6 Particle Size Diameter (μm) D(4, 3) 11 DV₁₀ 3 DV₅₀ 10 DV₉₀ 22

The Span of the particles (DV₉₀−DV₁₀)/DV₅₀ was 1.96. The bulk specificvolume of the particles was 5.6 cc/g, while the tapped specific volumewas 3.0 cc/g.

The glass-transition temperature (Tg) of the particles, measured at lessthan 5% relative humidity was 117.5° C. as measured by DifferentialScanning calorimetry (DSC). Powder X Ray diffraction (PXRD) showed theAPI to be amorphous, with no detectable crystallinity. The particlemorphology as measured by scanning electron microscopy (SEM) showed theparticles to have whole and collapsed spheres.

Example 6

Comparative Spray Dried Dispersion Tablet Tablets lacking awater-soluble acid were formed from the spray dried dispersion (SDD) ofExample 5 using the following procedure. Half the quantity ofmicrocrystalline cellulose was added to a blender (bin blender orequivalent), and mixed at low speed for approximately 25 revolutions (2minutes at 12 rpm). The SDD was added to the blender. The blender wasrinsed with a portion of sodium chloride and mixed.

Batch quantities of sodium chloride, croscarmellose sodium, andcolloidal silicon dioxide were added and mixed at low speed forapproximately 180 revolutions (15 minutes at 12 rpm). The final blend isgiven in Table 7.

TABLE 7 Component Amount (mg/tablet) Intragranular components SDD(Example 5) 357.143 Microcrystalline cellulose (Avicel PH-101) 191.657Sodium Chloride 191.200 Croscarmellose Sodium (AC-DI-SOL) 48.00Colloidal silicon dioxide (Cab-O-Sil MP5) 4.00 Magnesium Stearate 2.00Extragranular components Croscarmellose Sodium (AC-DI-SOL) 32.00Colloidal Silicon Dioxide (Cab-O-Sil M5P 4.00 Untreated) MagnesiumStearate 2.00 TOTAL 800.00

A mill and bag were pre-coated with 25 wt % of the quantity ofmicrocrystalline cellulose. The blend was passed from the above stepthrough the mill, using a Comil U5 equipped with a 1601 impeller, with ascreen size of 032R, and a speed of 1000 rpm. The mill was flushed withthe remaining batch portion of microcrystalline cellulose, the milledmaterial transferred from the bag to a blender (bin blender orequivalent) and mixed at low speed for approximately 180 revolutions (15minutes at 12 rpm).

The intragranular magnesium stearate was sieved through an appropriatelysized screen and added to the blender from the previous step then mixedat low speed for approximately 60 revolutions (5 minutes at 12 rpm).

The blend was compacted using a Korsch XP 1 or equivalent.

The compacted blend was passed through a mill using a Comil U5 equippedwith a 1601 impeller, with a screen size of 050G, and a speed 1000 rpm.

The granulation was transferred from the bag to a blender (bin blenderor equivalent). The amount of extragranular colloidal silicon dioxidewas calculated and added to the blender from the previous step thenmixed for approximately 180 revolutions (15 minutes at 12 rpm). Theamount of extragranular magnesium stearate required was calculated,sieved through an appropriately sized screen and added to the blenderfrom the previous step, then mixed for approximately 60 revolutions (5minutes at 12 rpm).

The tablets were compressed using a single station press (Korsch XP 1 orequivalent).

Example 7 Spray Dried Dispersion Tablet

Tablets were formed from the SDD of Example 5 using the followingprocedures. Half the quantity of microcrystalline cellulose was added toa blender (bin blender or equivalent), and mixed at low speed forapproximately 25 revolutions (2 minutes at 12 rpm). The SDD was added tothe blender and the blender was rinsed with a portion of sodium chlorideand mixed. The batch quantities of succinic acid, sodium chloride,croscarmellose sodium, and colloidal silicon dioxide were added andmixed at low speed for approximately 180 revolutions (15 minutes at 12rpm). The final composition of the blend is given in Table 8.

TABLE 8 Component Amount (mg/tablet) Intragranular components SDD(Example 5) 357.143 Microcrystalline cellulose (Avicel PH-101) 76.457Succinic Acid 143.20 Sodium Chloride 127.20 Croscarmellose Sodium(AC-DI-SOL) 48.00 Colloidal silicon dioxide (Cab-O-Sil MP5) 8.00Magnesium Stearate 2.00 Extragranular components Croscarmellose Sodium(AC-DI-SOL) 32.00 Colloidal Silicon Dioxide (Cab-O-Sil M5P 4.00Untreated) Magnesium Stearate 2.00 TOTAL 800.00

A mill and bag was pre-coated with 25 wt % of the quantity ofmicrocrystalline cellulose. The blend was passed from the above stepthrough the mill, using a Comil U5 equipped with a 1601 impeller, with ascreen size of 018R, and a speed of 1000 rpm. The mill was flushed withthe remaining batch portion of microcrystalline cellulose, the milledmaterial transferred from the bag to a blender (bin blender orequivalent) and mixed at low speed for approximately 180 revolutions (15minutes at 12 rpm).

The intragranular magnesium stearate was sieved through an appropriatelysized screen and added to the blender from the previous step, then mixedat low speed for approximately 60 revolutions (5 minutes at 12 rpm).

The blend was compacted using a Korsch XP 1 or equivalent.

The compacted blend was passed through a mill using a Comil U5 equippedwith a 1601 impeller, with a screen size of 050G, and a speed of 1000rpm. The amount of extragranular magnesium stearate required wascalculated, and sieved through an appropriately sized screen, and addedto the blender from the previous step. The mixture was mixed forapproximately 60 revolutions (5 minutes at 12 rpm).

The tablets were compressed using a single station press (Korsch XP 1 orequivalent).

Example 8 Dissolution Test 1 at pH 5.5

Test tablet formulations comprising the free base form of palbociclib(API), a water-soluble acid, microcrystalline cellulose (Avicel PH102),lactose monohydrate (Fast Flo 316), crospovidone (Kollidon CL), andmagnesium stearate were prepared for dissolution testing. Test tabletswere prepared using the dry granulation (DG) method described in Example1 for the following acids: malic acid, maleic acid, succinic acid,fumaric acid, tartaric acid, tosylic acid, benzoic acid andbenzenesulfonic acid. Test tablets were prepared via direct compression(DC) (without dry granulation) for malic acid and citric acid.

The tablets were dissolution tested in a USP 2 apparatus with paddlesspinning at 50 rpm, in 500 mL of 10 mM sodium acetate buffer at pH 5.5and a temperature of 37° C. At each pull point, 6 mL of sample wascollected and passed through a 10-μm full-flow filter. Analysis wasperformed off line at a UV wave length of 367 nm.

Comparative dissolution data were generated for the palbociclibisethionate salt (ISE) capsule and a free base API tablet prepared usingthe dry granulation method of Example 1, using a blend lacking thewater-soluble acid. The results of the dissolution test for tabletscomprising succinic acid, maleic acid, malic acid, fumaric acid andtartaric acid are shown in FIG. 1. Tablets comprising succinic acid,malic acid and tartaric acid exhibited superior dissolution performance,with greater than 50% of the drug dissolved at 30 minutes as shown inFIG. 2.

Example 9 Chemical Stability of Formulations

The test tablets prepared in Example 8 were stored at 70° C./75% RH for8 days. The tablets were crushed and analyzed for impurities using ahigh-performance liquid chromatography (HLPC) method as follows: WatersCSH C18, 2.1×100 mm, 1.7 μm column; mobile phase (gradient elution) A:0.03% trifluoroacetic acid, and B: 0.03% trifluoroacetic acid inacetonitrile; column temperature of 45° C.; flow rate of 0.5 mL/min; UVdetection at 234 nm; injection volume of 2 μL; and run time of 10.72minutes. The results are summarized in Table 9.

TABLE 9 Storage at 70° C./75% RH for 8 Days Formulation API Free APITotal Impurities Base plus an Acid (Area %) (Area %) Malic acid 99.350.645 Maleic acid 93.71 6.288 Succinic acid 98.81 1.190 Benzoic acid99.94 0.06 Tosylic acid 99.46 0.54 Tartaric acid 99.18 0.82 Citric acid97.18 2.82 Benzenesulfonic acid 99.55 0.45 Fumaric acid 91.94 8.06

Tablets comprising malic acid, succinic acid, benzoic acid, tosylicacid, tartaric acid and benzenesulfonic acid had acceptable totalimpurities after storage at 70° C./75% RH for 8 days. On the basis ofthe superior dissolution and stability experiments, formulationscomprising succinic acid, malic acid and tartaric acid were selected forfurther development.

Example 10 Non-Sink Dissolution Test 2

To screen the formulations, a non-sink in vitro dissolution method wasdeveloped. In this method, the tablets were placed into USP 2 (paddles)apparatus, with stirring at 50 rpm, and 500 mL of a 50 mM phosphatebuffer+0.1 M NaCl (pH 6.5), at a temperature of 37° C. Samples werecollected periodically, and filtered through 10-μm filters. Theconcentration of the API was measured off line at a UV of 367 nm.Dissolution data were generated for the tablets prepared in Example 1(FB+succinic, tablet), Example 2 (FB+succinic, bi-layer tablet), Example4 (FB+succinic, FBG tablet), Example 6 (SDD, tablet) and Example 7(SDD+succinic, tablet). Dissolution profiles are shown in FIG. 3. Alsoshown is the dissolution data for the commercial free base capsules ofpalbociclib (free base capsules) having the formulation in Table 10:

TABLE 10 125 mg Free base capsule Component Amount (mg/capsule)Palbociclib (mg) 125.000 Microcrystalline cellulose (mg) 185.917 Lactosemonohydrate 92.958 Sodium starch glycolate 27.000 Colloidal silicondioxide 10.125 Magnesium stearate 9.000 Total fill weight 450.000 Totalcapsule weight 546.000

As shown in FIG. 3, subjecting the dosage forms of Examples 1, 2 and 4to the non-sink dissolution conditions dissolves (a) not less than 40%of the palbociclib in 15 minutes; (b) not less than 35% of thepalbociclib in 30 minutes; (c) not less than 25% of the palbociclib in60 minutes; or (d) two or more of (a), (b) and (c).

Example 11 Drug Exposure Levels with Commercial Free Base Capsules

A randomized, single-dose, open-label, 4-sequence, 4-period cross-overstudy was run in healthy volunteers. Twenty-eight (28) subjects eachreceived a single dose of palbociclib 125 mg under 4 differentconditions or treatments (overnight fasted [A], high-fat meal predose[B], low-fat meal predose [C], and moderate-fat meal 1 hour before and 2hours post dose [D]).

The treatment sequences used for Periods 1 through 4 are presented inTable 11. There was a washout period of at least 10 days between studyperiods. Following treatment administration, subjects underwent PKsampling for 144 hours. The pharmacokinetic parameter values are givenin Table 12.

TABLE 11 Study Design Sequence Period 1 Period 2 Period 3 Period 4 1 (n= 7) A D B C 2 (n = 7) B A C D 3 (n = 7) C B D A 4 (n = 7) D C A B

TABLE 12 Parameter B: Fed C: Fed D: Fed (units) A: Fasted High Fat LowFat Moderate Fat N 28 28 27 28 AUC_(inf) (ng-hr/mL) 1408 1672 1573 1580AUC_(last) (ng-hr/mL) 1284 1627 1524 1533 T_(last) (hr) 119 119 118 119C_(last) (ng/mL) 39.22 53.67 50.20 48.64 T_(max) (hr) 8.00 8.00 8.008.00 T_(1/2) (hr) 23.9 22.1 22.0 22.9 CL/F (L/hr) 88.77 74.74 79.4579.10 V_(z)/F (L) 2993 2342 2475 2573

The palbociclib 125 mg commercial capsule formulation exhibited lowerAUC and C max when administered under fasted conditions relative to theexposure levels under the three fed conditions. Accordingly, it wasrecommended that the commercial capsule be administered with food.

Example 12 Effect of Antacid on Bioavailability of Palbociclib

The objective of this study was to investigate the potential effect ofincreased gastric pH achieved by the treatment of multiple doses of aproton pump inhibitor (PPI, specifically rabeprazole) on thepharmacokinetics (PK) of a single oral 125 mg commercial capsule ofpalbociclib given under fasted conditions.

The results are summarized in Table 13 below. The palbociclib 125 mgcommercial capsule formulation exhibited significantly lower AUC and Cmax when administered in the presence of rabeprazole relative toadministration of palbociclib alone.

TABLE 13 Palbociclib + Parameter (units) Palbociclib Alone RabeprazoleN, n 26, 26 25, 23 AUC_(inf) (ng-hr/mL) 1716 (45) 754.4 (38) AUC_(last)(ng-hr/mL) 1656 (47) 672.8 (40) T_(last) (hr) 120 (72.0-120) 96.0(72.0-120) C_(max) (ng/mL) 49.31 (72) 12.25 (44) T_(max) (hr) 7.00(6.00-24.0) 24.0 (6.00-48.0) T_(1/2) (hr) 21.97 ± 2.9721 22.45 ± 4.2139CL/F (L/hr) 72.85 (45) 165.7 (38) V_(z)/F (L) 2290 (49) 5289 (31)

Example 13 Effect of Antacid on Bioavailability of Test Formulations

A crossover, open label, non-randomized, pharmacokinetic study inhealthy volunteers was conducted to estimate the effect of antacidtreatment on the bioavailability of a 125 mg tablet (single dose) of sixexperimental formulations of palbociclib in the presence of rabeprazolerelative to administration of palbociclib alone under fasted conditions.Table 14(A)-(F) shows the results for Cohorts 1-6, Example 1; Example 6;Example 7; Example 2; Example 4; and 125 mg palbociclib oral solution,respectively.

TABLE 14 Plasma Adjusted Geometric Means Ratios PalbociclibPalbociclib + Palbociclib (Test/Reference) Parameters Rabeprazole Aloneof Adjusted 90% CIs [Units] (Test) (Reference) Means for Ratios (A)Summary results for Cohort 1 (tablets of Example 1). AUCinf [ng · hr/mL]1458 1449 100.61 (95.25, 106.27) Cmax [ng/mL] 45.91 49.25 93.22 (81.71,106.35) (B) Summary results for Cohort 2 (tablets of Example 6). AUCinf[ng · hr/mL] 1079 1120 96.31 (90.78, 102.18) Cmax [ng/mL] 36.54 39.8691.68 (80.91, 103.88) (C) Summary results for Cohort 3 (tablets ofExample 7). AUCinf [ng · hr/mL] 1548 1495 103.6 (94.39, 113.70) Cmax[ng/mL] 46.83 48.21 97.13 (84.41, 111.78) (D) Summary results for Cohort4 (tablets of Example 2) AUCinf [ng · hr/mL] 1443 1418 101.78 (94.95,109.09) Cmax [ng/mL] 45.18 47.50 95.12 (87.03, 103.96) (E) Summaryresults for Cohort 5 (tablets of Example 4) AUCinf [ng · hr/mL] 19621803 108.83 (103.64, 114.28)  Cmax [ng/mL] 64.91 62.52 103.83 (94.55,114.02) (F) Summary results for Cohort 6 (Oral solution) AUCinf [ng ·hr/mL] 1478 1451 101.83 (93.67, 110.69) Cmax [ng/mL] 47.77 50.24 95.07(85.18, 106.11)

Example 14 Accelerated Stability Tests

The tablets of Example 1 (dry granulation+succinic acid) were placed onaccelerated stability using the following conditions. Tablets were placeinto beakers at the conditions listed below. Humidity control wasachieved either through oven control or saturated salt solutions.Samples were removed from the conditions periodically as shown in Table15 below. Samples (including unexposed controls) were stored in arefrigerator until analysis.

The following saturated salt solutions maintained the designatedrelative humidity: 22% RH controlled via potassium acetate; 50% RHcontrolled via sodium bromide for the 30° and 40° C. conditions; and 75%RH via humidity controlled ovens.

TABLE 15 Temperature Relative Degradant* (° C.) Humidity (%) Time (days)(wt %) 0 0 0 (initial) 0 (initial) 30 22 96 0.05 30 50 96 0.07 30 75 960.12

The degradant is the succinyl adduct of the API, having the structure:

Samples were prepared by adding each tablet to a 100 mL volumetricflask, adding a stir bar and approximately 100 mL of the dissolvingsolvent (1440 mL water:400 mL acetonitrile:160 mL 1N HCl; 0.1 N HCl:acetonitrile 80:20). The flask was placed on a stir plate and sample wasstirred for one hour at the highest useable stir speed. An aliquot wasthen removed and centrifuged in a polypropylene tube at 3000 RPM for 5minutes. The supernatant was diluted 1:5 with dissolving solvent andsampled into an HPLC vial for analysis. Each tablet contained 125 mg APIfor a final solution concentration of 0.25 mg/mL. The samples wereanalyzed using the HPLC method below. The results are presented in Table15 above, and show excellent long-term stability.

Dissolving Solvent (Diluent):

1440 mL water: 400 mL acetonitrile: 160 mL 1N HCl//(0.1 N HCl:acetonitrile 80:20) Mobile Phase:

Mobile Phase A: 0.03% trifluoroacetic acid (0.6 mL of trifluoroaceticacid into 2000 mL of water)

Mobile Phase B: 0.03% trifluoroacetic acid in acetonitrile (0.6 mL oftrifluoroacetic acid into 2000 mL of acetonitrile) 0.5 mL/min

Gradient Initial 88% A 12% B 0.22 min 88% A 12% B 8.72 min 15% A 85% B8.82 min 88% A 12% B 10.72 min  Total run time2 μL injection of samples (prepared as directed below). Sample chambermaintained at 5° C.

Sample Preparation

Samples were prepared by adding each tablet to a 100 mL volumetricflask, adding a stir bar and approximately 100 mL of the dissolvingsolvent. The flask was placed on a stir plate and sample was stirred forone hour at the highest useable stir speed. An aliquot was then removedand centrifuged in a polypropylene tube at 3000 RPM for 5 minutes. Thesupernatant was diluted 1:5 with dissolving solvent and sampled into anHPLC vial for analysis. Each tablet contained 125 mg palbociclib for afinal solution concentration of 0.25 mg/mL.

In addition, the tablets of Example 4 (fluid bed granulation+succinicacid) were analyzed in the same manner. The results are presented in thefollowing Table 16, and show that the degradant concentration wasunacceptable for long-term stability.

TABLE 16 Temperature Relative Degradant* (° C.) Humidity (%) Time (days)(wt %) 0 0 0 (initial) 0 (initial) 30 22 96 0.211 30 50 96 0.263 30 7596 0.444 *The degradant is the succinyl adduct of the API

Example 15 Long Term Storage Stability

The tablets of Example 1 were packaged with a desiccant canister in abottle using a heat-induction seal. After storage for 1 year at 25°C./60% RH, the tablets had a succinyl adduct level of less than 0.05%.The tablets of Example 4 were packaged with a desiccant canister in aHDPE bottle using a heat-induction seal. After storage for 6 months at25° C./60% RH, the tablets had a succinyl adduct level of 0.23%.

Example 16 Film Coated Tablet Formulations

Table 17 describes optimized Formulations A1, A2 and B, which showedacceptable manufacturing performance for solid dosage formcommercialization. The tablets were formed using the followingprocedure. The microcrystalline cellulose PH102, colloidal silicondioxide, intragranular crospovidone CL, and API were blended togetherand passed through a Comil for homogenization. Intragranular magnesiumstearate was blended in. The mixture was dry granulated using rollercompaction and granule milling.

Sieved succinic acid, microcrystalline cellulose PH-200, andextragranular crospovidone (CL or CL-SF grade) were blended into thegranules. Extragranular magnesium stearate or sodium stearyl fumaratewas mixed into the final blend as a tableting lubricant. Tablets wereformed using a rotary tablet press with pre-compression. Formulation A2used an external lubrication system (ELS) to apply a nominal amount oflubricant directly to the tablet punch tips.

Tablets were film coated to a weight gain of 2 to 4% using Opadry Pink(03K140024) and purified water to a solids content of 12% w/w.

TABLE 17 Optimized formulations Quantity/unit: (mg/tablet) FormulationFormulation Formulation Component: A2 A1 B Intragranular ComponentsPalbociclib (API) 125.000 Microcrystalline Cellulose 244.812 (AvicelPH102) Colloidal Silicon Dioxide 6.250 (Aerosil 200 Pharma) Crospovidone(Kollidon CL) 18.750 Magnesium Stearate 2.063 Extragranular ComponentsSuccinic Acid extra pure, 62.500 (100 to 350 micron) MicrocrystallineCellulose 143.750 134.375 115.625 (Avicel PH-200) Crospovidone (KollidonCL 18.750 18.750 or CL-SF) (CL) (CL-SF) Sodium Stearyl Fumarate — 31.250(PRUV) Magnesium Stearate 3.125 12.500 — (standard or fine grade)(standard) (fine) Tablet Core 625.000 Opadry Pink (03K140024) 18.750Purified Water (removed (137.500) during final processing) Final CoatedTablet 643.750

Example 17 Optimization of Lubricant Level

Formulations were prepared as described for Formulation A2 in Example 16with different levels of intragranular and extragranular magnesiumstearate lubricant, as shown in Table 17. Hardness (tablet breakingforce, USP <1217>), friability (USP <1216> for 100 revolutions),extended friability (USP <1216> for 375 revolutions), and punch sticking(Hutchins, MacDonald, Mullarney, Assessing Tablet-Sticking Propensity,Pharmaceutical Technology, Volume 36, Issue 1, 2012) were measured foreach formulation as reported in Table 18. Reduced sample sizes were usedfor the USP methods.

Reducing both the intragranular and extragranular lubricant levelssignificantly increased tablet hardness and reduced friability. Tabletsticking was more sensitive to extragranular lubricant level thanintragranular lubricant level. Sticking was significantly reduced byincreasing extragranular magnesium stearate level. No difference inknurled/smooth roller sticking was observed with different intragranularmagnesium stearate levels. As shown in Table 18, reducing theintragranular/extragranular lubricant ration from 1 wt %/0 wt % to 0.33wt %/0.5 wt % provided with good tablet strength, reduced friability,and reduced sticking for tablets of Formulation A2. Lubricant levels ofabout 5 wt % sodium stearyl fumarate or 2 wt % fine grade stearate (CaSt2249) alleviated punch sticking and tablet defects.

TABLE 18 Optimization of lubricant level. Extra- Intragranular granularExtended Lubricant Lubricant Hardness Friability friability StickingLevel (%) Level (%) (kP) (%) (%) (ug) 0.33 0 22 0.08 0.23 2914 0.5 190.09 0.28 766 1 16 0.15 0.54 304 0.67 0 21 0.13 0.45 1977 0.5 18 0.130.38 563 1 16 0.11 0.49 142 1 0 18 0.00 0.36 1346 0.5 18 0.09 0.43 428 115 0.14 0.57 242

Example 18 Optimization of Tablet Hardness and Friability

Formulations were prepared as generally described for Formulation A2 inExample 16, with changes to the order of addition of acid, addition oflactose monohydrate, addition of dry binders (Kollidon SF, Avicel PH105,Klucel EXF), and change in the intragranular to extragranular ratio ofmicrocrystalline cellulose. The properties of these differentformulations were measured: initial blend bulk density (USP <616>),roller compacted ribbon tensile strength (Zinchuk A V, Mullarney M P,Hancock B C. Simulation of roller compaction using a laboratory scalecompaction simulator. Int J Pharm. 2004 Jan. 28; 269(2):403-15.), punchsticking (Hutchins, MacDonald, Mullarney, Assessing Tablet-StickingPropensity, Pharmaceutical Technology, Volume 36, Issue 1, 2012), tablethardness (tablet breaking force, USP <1217>), friability (USP <1216> for375 revolutions), and disintegration time (USP <701>). Reduced samplesizes were used for the USP methods.

Formulations without lactose showed higher tablet hardness and lowerfriability. Additionally, adding the SF (superfine) grade of Kollidonhelped decrease disintegration time while increasing tablet hardness.Adding the acid extragranularly was found to be preferable to obtainshorter disintegration times.

Removal of lactose from the formulation provided tablets having reducedfriability which maintained rapid disintegration. The inclusion of drybinders did not provide additional benefit to reducing friability, butmarginally reduced sticking. However, the inclusion of binders can insome cases negatively impact disintegration/swelling.

TABLE 19 Optimization of diluent and binder components Initial Ribbonblend bulk Tensile density Strength Sticking Hardness Friability Disint.Time Example (g/cc) (MPa) (ug) (kp) (%) (m:s) Control 0.33 1.4 1074 160.44  1:51 (incl. lactose) Remove lactose 0.31 1.8 1029 20 0.27  2:41Move Acid 0.40 1.0 N/A 19 0.21  8:15 from EG to IG (incl. lactose) AddKollidon 0.24 3.1 728 22 0.37  1:20 SF (no lactose) Add Avicel 0.31 2.1975 19 0.47  2:26 PH105 (no lactose) Add Klucel 0.31 1.5 842 18 0.2550:41 EXF (no lactose) Move EG 0.33 2.8 1392 18 0.28 03:30 Avicel to IG(no lactose)

Example 19 In Vitro Dissolution of Formulations A1, A2 and B

In vitro dissolution of optimized formulations A1, A2 and B wasdetermined using Dissolution Test 2, under the non-sink conditions (pH6.5, 50 mM phosphate buffer, 0.1 M NaCl) described in Example 10. Thedissolution profiles of these formulations were compared to the tabletsprepared according to Examples 1-7. The tablet of Example 1 showed nodrug-drug interaction with a proton pump inhibitor in the fasted statein human volunteers and was set as the minimum target dissolutionprofile. Comparative dissolution data are presented in FIG. 4.Formulations A1, A2 and B were all superior to both the commercial freebase capsules (prepared as described in Example 10) and the palbociclibisethionate salt (ISE) capsules used in early development having theformulation in Table 20, After 10 minutes, the formulations A1, A2 and Bwere all superior to the tablets of Examples 1-7, and therefore met thesolid dosage form dissolution target.

TABLE 20 25 mg ISE 100 mg ISE capsule capsule Amount Amount Component(mg/capsule) (mg/capsule) Palbociclib isethionate (mg) 32.048 128.200(eq. 25 mg FB) (eq. 100 mg FB) Microcrystalline cellulose (mg) 102.802148.500 Sodium starch glycolate 8.700 13.500 Magnesium stearate 1.4502.300 Corn starch 145.000 157.500 Total fill weight 290.00 450.000

Example 20 Impact of Succinic Acid Particle Size Distribution

The impact of succinic acid particle size distribution on the rate offormation of the succinyl adduct was assessed for as-received acid(broad particle size distribution up to 1 mm diameter) and three sievecuts of the acid. Smaller acid particle size resulted in a greater rateof impurity formation because of its larger specific surface areaenabling a higher frequency of contacts of the acid with the free baseAPI. Therefore acid with a particle size greater than approximately 100microns was preferred in the drug product formulation to improvechemical stability.

TABLE 21 Impact of succinic acid particle size distribution on adductformation Acid degradation rate (%/year) Storage As-received Acid AcidAcid Condition acid, without sieved to sieved to sieved to (° C./% RH)sieving <106 μm 150-250 μm 425-600 μm 25° C./22% RH 0.092 0.150 0.0710.035 25° C./60% RH 0.253 0.346 0.167 0.082 30° C./22% RH 0.203 0.2940.150 0.075 30° C./75% RH 0.837 0.942 0.494 0.249

Example 21 Physical Stability Analysis

A quantitative Raman spectroscopic method was developed to evaluate thephysical stability of the formulations. The Raman method uses a KaiserOptical Systems PhAT probe and the quantitation model was builtutilizing a set of calibration standards prepared from API, APIsuccinate complex and excipients. The relative stability of FormulationsA1 and B were assessed by determining the amount of API succinatecomplex in the formulation after storing the tablets at 30 to 50° C. andup to 75% RH for up to 1 month.

Formulation B showed lower conversion to the succinate complex relativeto Formulation A1. The amount of conversion increased over time and wasaccelerated by storage conditions with higher temperature and humidity.

The amount of API succinate complex formed under various temperature andhumidity conditions for formulation A1 and B is shown in Table 22 as afunction of time, where “LOD” refers to the limit of detection and “LOQ”refers to the limit of quantification.

TABLE 22 Conversion of free base API to API succinate complex Storage 2weeks 2 weeks 1 month 1 month Condition Formulation FormulationFormulation Formulation (° C./% RH) A1 B A1 B Initial <2% (LOD) <2%(LOD) <2% (LOD) <2% (LOD) 50/75 56% 32% — — 50/low <5% (LOQ) <5% (LOQ) —— 40/75 — — 56% 33% 30/75 — — 13% 10%

The physical stability of prototype non-coated tablet formulation A1under open conditions was assessed. Tables were subjected to elevatedtemperatures and humidity. Conversion to the succinate complex wasobserved in stressed samples using Raman spectroscopy.

The chemical purity of Formulations A1 and B were compared after storagefor 1 month at 40° C./75% RH. As shown in Table 23, Formulation B showeda significantly lower extent of total impurity formation relative toFormulation A1.

TABLE 23 Degradation of Formulations A1 and B after 1 month at 40 C./75%RH Formulation A1 Formulation B Impurity % Impurity % Impurity Oxidativedegradant 1 0.15% NMT Oxidative degradant 2 0.19% 0.05% Fumarate adductND 0.15% Oxidative degradant 3 0.35% 0.07% Unidentified degradant 0.13%ND Oxidative degradant 4 0.38% 0.08% Succinyl adduct 0.18% 0.18%Oxidative degradant 5 0.21% NMT Formyl adduct 0.45% 0.15% Total Impurity2.1% 0.75%

Based on these data, humidity (% RH) was determined to have asignificant impact on the rate of API conversion from free-base tosuccinate complex. Increasing temperature also impacted conversion tothe complex, but had a weaker effect than humidity.

Tablets which were pre-equilibrated in 60% RH before foil-foil packagingdisplayed rapid succinate complex formation. The 9 week stability dataindicated that control of water activity in tablets was required tominimize formation of the palbociclib succinate complex in the drugproduct. Formulation B (which contains extragranular sodium stearylfumarate as the lubricant) showed less succinate complex conversion incomparison to formulation A1 (which incorporates magnesium stearate asthe extragranular lubricant) under conditions of high humidity (75% RH).

We claim:
 1. A solid dosage form comprising from about 10 wt % to about35 wt % of palbociclib, from about 5 wt % to about 25 wt % of awater-soluble acid selected from the group consisting of succinic acid,malic acid and tartaric acid, and a pharmaceutically acceptable carrier.2. The solid dosage form of claim 1, wherein the water-soluble acid issuccinic acid.
 3. The solid dosage form of claim 1, wherein thepharmaceutically acceptable carrier comprises at least one diluent, andwherein the diluent comprises about 50 wt % to about 75 wt % of thesolid dosage form.
 4. The solid dosage form of claim 3, wherein thediluent is selected from the group consisting of microcrystallinecellulose, lactose monohydrate, mannitol, sorbitol, xylitol, magnesiumcarbonate, dibasic calcium phosphate and tribasic calcium phosphate. 5.The solid dosage form of claim 1, wherein the pharmaceuticallyacceptable carrier comprises at least one lubricant, and wherein thelubricant comprises from about 0.5 wt % to about 10 wt % of the soliddosage form.
 6. The solid dosage form of claim 5, wherein the lubricantis selected from the group consisting of magnesium stearate, calciumstearate, zinc stearate and sodium stearyl fumarate.
 7. The solid dosageform of claim 1, wherein the pharmaceutically acceptable carriercomprises at least one disintegrant, and wherein the disintegrantcomprises from about 5 wt % to about 10 wt % of the solid dosage form.8. The solid dosage form of claim 7, wherein the disintegrant isselected from the group consisting of crospovidone, croscarmellosesodium and sodium starch glycolate.
 9. The solid dosage form of claim 1,in the form of a tablet.
 10. The solid dosage form of claim 9, whereinthe tablet is film coated.
 11. The solid dosage form of claim 9, whereinthe tablet is a bilayer tablet.
 12. The solid dosage form of claim 1,wherein the dosage form when added to a test medium comprising 500 mL of10 mM pH 5.5 acetate buffer at 37° C. in a standard USP 2 rotatingpaddle apparatus with the paddles spinning at 50 rpm dissolves: (a) notless than 35% of the palbociclib in 15 minutes; (b) not less than 45% ofthe palbociclib in 30 minutes; (c) not less than 55% in 60 minutes; or(d) two or more of (a), (b) and (c).
 13. The solid dosage form of claim1, wherein the dosage form when added to a test medium comprising 500 mLof 50 mM pH 6.5 phosphate buffer and 0.1 M NaCl at 37° C. in a standardUSP 2 rotating paddle apparatus with the paddles spinning at 50 rpmdissolves: (a) not less than 40% of the palbociclib in 15 minutes; (b)not less than 35% of the palbociclib in 30 minutes; (c) not less than25% of the palbociclib in 60 minutes; or (d) two or more of (a), (b) and(c).
 14. A solid dosage form of claim 1, wherein the dosage form: (a)has a mean fed/fasted ratio of the area under the plasma concentrationversus time curve (AUC) from about 0.8 to about 1.25 afteradministration of a single oral dose to a subject; (b) has a meanfed/fasted ratio of the maximum plasma concentration (C_(max)) fromabout 0.8 to about 1.25 after administration of a single oral dose to asubject; or (c) both (a) and (b).
 15. The solid dosage form of claim 1,wherein the dosage form: (a) provides a mean fasted AUC in the range of80% to 125% of the mean fasted AUC for a control immediate release (IR)oral capsule containing an equivalent amount of palbociclib afteradministration of a single oral dose to a subject; (b) provides a meanfasted C_(max) in the range of 80% to 125% of the mean fasted C_(max)for a control immediate release (IR) oral capsule containing anequivalent amount of palbociclib after administration of a single oraldose to a subject; or (c) both (a) and (b).
 16. The solid dosage form ofclaim 1, wherein the dosage form provides: (a) a mean AUC in thepresence of a proton pump inhibitor (PPI) in the range of 80% to 125% ofthe mean AUC in the absence of the PPI after administration of a singleoral dose to a subject; (b) a mean C_(max) in the presence of a protonpump inhibitor (PPI) in the range of 80% to 125% of the mean C_(max) inthe absence of the PPI after administration of a single oral dose to asubject; or (c) both (a) and (b).
 17. The solid dosage form of claim 16,wherein the PPI is rabeprazole.
 18. The solid dosage form of claim 1,wherein the dosage form exhibits less than 0.05% acid adduct by weightafter storage for 1 years at 25° C. and 60% RH.
 19. The solid dosageform of claim 1, wherein the amount of palbociclib in the dosage form is25 mg, 75 mg, 100 mg or 125 mg.
 20. The solid dosage form of claim 19,wherein the amount of palbociclib in the dosage form is 125 mg.